The renin-angiotensin system has long been suspected of being involved in the pathogenesis or maintenance of hypertensive diseases. A firm correlation has been found for renovascular hypertension, where excess renin release from the kidney has been documented, and for oral contraceptive-induced hypertension where the correlation is with excess angiotensinogen. However, attempts to document the role of the renin-angiotensin system in essential hypertension have not been successful. In addition, the renin-angiotensin system has been implicated in other diseases such as preeclampsia, stroke, hepatorenal syndrome and sarcoidosis. The one component of the system frequently found to correlate with hypertension is elevated levels of angiotensinogen. This serum glycoprotein, released from the liver, is the precursor of angiotensin. Our findings of heterogeneity of human angiotensinogen and our demonstration that the protein is present in extravascular brain tissue provides a new concept to the pathological involvement of the renin-angiotensin system. We will examine the role of angiotensinogen by characterizing the molecular basis and pathophysiological importance of the heterogeneity and document levels of the forms of the protein in both clinical and experimental studies. Further we will critically examine the components of a central nervous system angiotensin I generating pathway and evaluate its contribution to disease states.